Abstract: Anterior cruciate ligament (ACL) reconstruction is the 6th most common orthopaedic procedure performed in the United States, with more than 130,000 ACL reconstructions performed annually. While ACL reconstruction is often considered successful, many patients do not return to pre-injury functional levels (skeletal muscle), and the procedure does not appear to be effective for preventing osteoarthritis (OA). These muscle strength deficits are associated with changes in muscle physiology and structure, including atrophy, infiltration of senescent cells, reduction in muscle progenitor cells (MPCs) and the development of fibrotic tissue through the activation of fibrogenic-adipogenic progenitor (FAPs). In fact, accumulation/infiltration of senescent cells occurs in aging-associated muscle atrophy/sarcopenia, impairing muscle function. We believe that senescent cell accumulation also occurs after ACL injury/surgery, interfering with muscle recovery. Thus, novel biological interventions may be necessary to supplement conventional rehabilitation approaches in order to specifically address muscle histopathology and fully restore muscle function after ACL injury/surgery. Our laboratory has investigated multiple biological strategies for improving muscle healing after a variety of injuries, diseases and aging. We have shown that promotion of angiogenesis is one of the most efficacious strategies to improve muscle healing after injury. One such approach, muscle-specific over-expression of estrogen-related receptor gamma (ERR-?), recapitulates exercise by transcribing a pro-angiogenic gene program that increases muscle vascularization. We posit that this exercise-mimetic pathway may highlight a new concept and help in the development of novel, non-invasive rehabilitation strategies for restoring muscle function after ACL injury. In Aim 1, we will investigate whether muscle histopathology after ACL injury/surgery is associated with the infiltration of senescent cells, a functional defect in MPCs and over-activation of FAPs, as well as whether ERR- ? activation prevents these muscle histopathological cellular events after ACL surgeries. In Aim 2, we will determine correlations between muscle weakness, reduction in muscle regeneration and angiogenesis, and the development of fibrosis, and investigate whether exercise mimicry via ERR-? activation via the use of our transgenic mice, can create resistance to muscle weakness, using our ACL injury model. Our ERR? transgenic mice, engineered to enhance skeletal muscle vascularization, will be a powerful new tool for investigating the link between muscle vascularity, muscle/fibrotic progenitor cells, senescent cells, and muscle weakness after ACL injury. Muscle atrophy and degeneration are major contributors to poor outcomes for a wide range of musculoskeletal disorders, including joint replacement and rotator cuff tears as well as knee injuries. Pharmacological approaches for stimulating angiogenesis and/or reducing senescent cells (using currently available senolytic drugs) have tremendous potential to improve outcomes in many patients after ACL injury/surgery for whom physical therapy alone fails to restore pre-injury muscle function.